Poster Presentation BACPATH 2022

Wollamide cyclic hexapeptides synergise with tuberculosis antibiotics in targeting Mycobacterium tuberculosis (#145)

Rachel F Rollo 1 , Giorgia Mori 1 , Tim A Hill 2 3 , Doris Hillemann 4 , Susanne Homolka 5 , Robert J Capon 3 , David P Fairlie 1 , Antje Blumenthal 1 6
  1. University of Queensland Diamantina Institute, The University of Queensland , Brisbane, QLD, Australia
  2. Australian Research Council of Excellence in Advanced Molecular Imaging, Institute for Molecular Biosciences, The University of Queensland , Brisbane, QLD, Australia
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  4. National and WHO Supranational Reference Center for Mycobacteria, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
  5. Molecular and Experimental Mycobacteriology, Priority Area Infections, Research Center Borstel, Leibniz Lung Center, Borstel, Germany
  6. Australian Infectious Diseases Research Centre, The University of Queensland , Brisbane, QLD, Australia

The TB global health crisis is aggravated by the rise of multi- and extensively drug-resistant Mycobacterium (M.) tuberculosis. Priorities for reducing the global burden of TB and meeting targets of the End TB strategy include improved treatment regimens with new options for drug-resistant TB. Current TB treatment require multiple antibiotics and any new treatment regimens are likely to comprise multiple agents. Thus, new antitubercular candidates require assessment of potential beneficial and detrimental interactions with existing TB antibiotics. Here we assessed how current TB antibiotics interact with wollamides, a recently reported class of Streptomyces-derived cyclic hexapeptides with anti-mycobacterial activity. For growth studies, antibiotics were combined with wollamides in a checkerboard method and the inhibition of growth measured after 10 days incubation. Interaction scores were calculated using the fractional inhibitory concentration index (FICI) and the zero-interaction potency (ZIP) model. Bactericidal activity was measured by decrease in log2 CFU/mL after 10 days exposure to antibiotics. We show that wollamides synergise with the first- and second-line antibiotics ethambutol, pretomanid, delamanid, and para-aminosalicylic acid in their bacteriostatic and bactericidal activities against phylogenetically diverse clinical and reference strains of M. tuberculosis, including multidrug- and extensively-drug resistant isolates. Wollamides do not antagonise the first-line TB antibiotics isoniazid and rifampicin, or combinations of isoniazid/rifampicin +/- ethambutol. Moreover, wollamides showed neutral interactions with the new combination regimen for multidrug-resistant TB, bedaquiline, pretomanid and linezolid (BPaL). Our data encourage further exploration of the wollamide pharmacophore as a lead for new TB antibiotics.